Understanding and controlling asthma in Latin America: A review of recent research informed by the SCAALA programme

Abstract Asthma is an important health concern in Latin America (LA) where it is associated with variable prevalence and disease burden between countries. High prevalence and morbidity have been observed in some regions, particularly marginalized urban populations. Research over the past 10 years from LA has shown that childhood disease is primarily non‐atopic. The attenuation of atopy may be explained by enhanced immune regulation induced by intense exposures to environmental factors such as childhood infections and poor environmental conditions of the urban poor. Non‐atopic symptoms are associated with environmental and lifestyle factors including poor living conditions, respiratory infections, psychosocial stress, obesity, and a diet of highly processed foods. Ancestry (particularly African) and genetic factors increase asthma risk, and some of these factors may be specific to LA settings. Asthma in LA tends to be poorly controlled and depends on access to health care and medications. There is a need to improve management and access to medication through primary health care. Future research should consider the heterogeneity of asthma to identify relevant endotypes and underlying causes. The outcome of such research will need to focus on implementable strategies relevant to populations living in resource‐poor settings where the disease burden is greatest.

factors increase asthma risk, and some of these factors may be specific to LA settings. Asthma in LA tends to be poorly controlled and depends on access to health care and medications. There is a need to improve management and access to medication through primary health care. Future research should consider the heterogeneity of asthma to identify relevant endotypes and underlying causes. The outcome of such research will need to focus on implementable strategies relevant to populations living in resource-poor settings where the disease burden is greatest.

K E Y W O R D S
allergy, asthma, determinants, Latin America

| INTRODUCTION
Asthma is the most common chronic respiratory disease (CRD) worldwide and is estimated to affect 262 million causing significant mortality and morbidity, 1 and has emerged as an important public health problem in many Latin American (LA) countries over the last 30 or so years. LA is a highly diverse region in terms of geography, climate, wealth, and ethnicity including 20 different countries with 639 million inhabitants, where 40 million are estimated to have asthma. 2 A common feature of LA countries is the high level of social inequalities 3 (Figure 1). In LA, asthma prevalence in both children and adults is highly variable and, where high, is among the highest worldwide, particularly in coastal tropical cities. 4 In the present review, we discuss progress in our understanding of how social, environmental and host genetic factors affect asthma prevalence, morbidity, and mortality in LA with a particular focus on the findings of SCAALA (Social Changes, Asthma, and Allergies in Latin America), an ongoing asthma research programme in Brazil and Ecuador. 5,6 This review does not consider the specific role of several important exposures such as air pollutants on asthma, or findings in Hispanic populations living in the United States and associated territories, that have been covered comprehensively elsewhere. 7-10 2 | EPIDEMIOLOGY OF ASTHMA AND DISEASE BURDEN

| Asthma prevalence
The ISAAC studies (International Study of Asthma and Allergies in Children) reported a high prevalence of asthma symptoms (≥20%) and severe asthma (≥7.5%) in adolescents living in LA cities. 11 The prevalence of asthma symptoms between countries ranged from 6.6% in Cuernavaca, Mexico, to 27.1% in Salvador, Brazil. Over half of LA countries reported a prevalence of 15% or more in children. 4 Extensive national surveys of asthma prevalence in representative samples of Brazilian adolescents confirmed a high prevalence of recent symptoms (23.2%) in 2012, ranging from 16.8% in Salvador to 27.3% in Porto Alegre, 12 but which had declined in a repeat survey in 2015. 13 Ecological studies of children 14 and adolescents 15 across LA cities suggested that social inequalities were a major determinant of asthma prevalence.

| Non-atopic asthma is predominant
A consistent observation across population-based studies of children with asthma in LA and other low and middle-income country (LMIC) settings has been the relatively weak associations with atopy. ISAAC phase II estimated approximately 40% of asthma to be attributable to F I G U R E 1 Latin American societies are highly unequal: underserved neighbourhood and affluent high-rise apartment buildings in the City of Salvador, Brazil. The hygiene hypothesis was proposed to explain temporal trends of increasing prevalence of asthma and allergic diseases. 27 Such trends were explained by reduced exposures to infectious diseases and environmental microbes during early childhood. The hypothesis was believed to operate through immunological mechanisms in which early life microbial exposures provided key signals for the maturation of the immune response-children living in more hygienic circumstances were considered to receive insufficient microbial signals resulting in delayed immune maturation and the induction of less robust immune regulation making them more vulnerable to inflammatory diseases such as asthma. 28,29 Similarly, children born and brought up on traditional European farms had a reduced risk of atopy and asthma compared to children not living on farms, and this protection was attributed to intense exposures to a wide diversity of microbial products such as endotoxin on farms. [30][31][32] The observations of a greater risk of asthma in poor inner-city neighbourhoods in the United States and in marginalized urban populations in LA where, presumably, hygienic conditions were less than optimal, was taken as evidence against a role for this hypothesis. 33 3.1.2 | Poor hygiene exposures and immune regulation Initial observations from underprivileged neighbourhoods in Salvador, Northeast Brazil, showed that poor environmental hygiene (such as living in a household without a sewage or tap water connection, and unpaved streets) 34 and being infected with geohelminth parasites were associated with greater in vitro production of the immune regulatory cytokine, IL-10, by peripheral blood leucocytes (PBLs). [35][36][37] Elevated IL-10 regulated both Th1 and Th2 responses in this population. Studies in Ecuador of children living in traditional riverine communities and underserved urban neighbourhoods in the coastal Province of Esmeraldas showed that IL-10 production by PBLs was greater in urban children 36,37 and that poor hygiene exposures, including geohelminth infections, were associated with cytokine response phenotypes suggestive of a hyporesponsive innate and modified Th2 (an immune response defined by the presence of both Th2 cytokines and IL-10) adaptive responses. The hyporesponsive innate phenotype was associated with reduced SPT. 37 Interestingly, there was evidence of a doseresponse effect of helminth infection such that an increasing number of helminth species infecting children was associated with increased IL-10 but reduced SPT. 38 Together these data indicate that poor hygiene exposures, likely to be most intense in poor urban neighbourhoods, are associated with increased immune regulation that minimizes allergic inflammatory responses (e.g SPT) but with minimal effects on asthma symptoms.

| Parasites and asthma/atopy
Longitudinal analyses in both urban Salvador and rural coastal Ecuador showed that early life infections with geohelminths, particularly Trichuris trichiura, were associated with a reduced prevalence of SPT later in childhood. 39,40 Effects of geohelminths on asthma symptoms have been less consistent. In general, strong effects on prevalence of asthma symptoms have not been observed in crosssectional analyses. 41,37 However, longitudinal analyses of children in rural Ecuador showed contrasting parasite-specific effects on risk of asthma symptoms in later childhood, with early childhood T. trichiura decreasing and Ascaris lumbricoides increasing risk. 24 There is strong evidence that allergic sensitization to Ascaris (measured by the presence of anti-Ascaris IgE) is associated with asthma symptoms and disease severity. 19,[43][44][45][46][47] The presence of anti-Ascaris IgE explained a higher frequency of asthma symptoms in rural compared to urban children (PAF%, 49.7 vs. 39.4%). 19 In the case of urban children, particularly those with more severe illness, a much higher proportion of symptoms was explained by mite rather than Ascaris sensitization. 17,45 The observations that A. lumbricoides can cause severe lung disease in murine models 48,49 and that IgG seropositivity to Ascaris spp. in males living in Northern Europe is associated with impaired lung function, 50 indicate the need for studies addressing potential effects of ascariasis on CRD in endemic settings in LA. COOPER ET AL.

| Common childhood infections and asthma/ atopy
An analysis of exposures to childhood infectious diseases among children in Salvador showed that seropositivity to a variety of common bacteria, viruses, and parasites including active geohelminth infections, were inversely associated with SPT but not associated with reduced asthma symptoms. 51 Further, a greater burden of common childhood infections in this population and markers of poor environmental hygiene (e.g. low maternal education and unpaved streets) were associated with an under-responsive cytokine phenotype characterized by low or negligible production of Th1, Th2, and Treg cytokines and a lower prevalence of SPT. 48 There was evidence that this effect was mediated by cytokine phenotype, but immune response phenotypes and poor hygiene exposures were not associated with asthma symptoms. 52 These findings show clearly that poor hygiene exposures, including childhood infections, induce immune phenotypes in children that reduce inflammatory responses and the risk of allergic sensitization as indicated by a positive SPT but have little impact on asthma symptoms.
The predominance of non-atopic asthma in LA populations, likely mediated by distinct causal mechanisms to that of atopic disease, could explain a high prevalence of symptoms despite intense unhygienic exposures. In fact, such exposures have been associated with an increased risk of non-atopic wheeze in these populations. 17,41,42

| Urbanization and asthma
Urbanization refers to the complex and gradual processes by which populations become urban and includes population growth by migration and natural increases resulting in greater population densities, improvements in built infrastructure, and changes in social and economic activities and lifestyles. 53 The LA population is now predominantly urban (overall 81%), a proportion that is much greater in Brazil [87%] than Ecuador [64%]. 54 The study of the effects of urbanisation on asthma is complex because of the multidimensional nature of this process and the methodological and conceptual limitations in defining and measuring urbanisation.
Much of the evidence supporting a relationship between urbanisation and asthma is derived from prevalence studies comparing rural and urban populations. 39 Such studies cannot disentangle specific urbanization features linked to asthma. 55

| Multidimensional measures of urbanization and urbanicity
In urban studies, an alternative is to use a multidimensional approach to define urbanisation using composite measure of urbanicity (i.e., presence of conditions that are more common in urban areas at any given time) 53 based on indicators such as urban infrastructure, F I G U R E 2 Forest plot of 13 observational studies comparing asthma prevalence between urban and rural populations in Latin America. Shown is a pooled Odds ratio across studies of 1.52. socioeconomic characteristics, and demographic and geographic features. Two asthma-related studies (an ecological and a crosssectional study) have used this approach in transitional populations in Ecuador, 39,70 and showed an increasing asthma prevalence with greater levels of urbanisation.
The process of urbanisation has a profound impact on the lifestyle of populations not only in urban but also in rural areas ( Figure 3). Changes in, for example, dietary patterns, health behaviours, work activities, economic status, and housing materials, are all related to the urbanisation process. 71 Although lifestyle changes have been associated with increased asthma and differences in asthma prevalence between rural and urban populations, it has been difficult to disentangle independent effects of individual risk factors that together constitute lifestyle. To overcome this limitation, an analysis of childhood asthma in Ecuador in which lifestyle was defined as a set of attributes representing groups of linked risk factors, identified lifestyle domains relating to home infrastructure and sedentarism as being most strongly associated with wheeze in urban and rural areas. 72

| Internal migration
Internal migration is a key process contributing to urbanisation that asthma studies in LIMCs have largely overlooked. The migration F I G U R E 3 Urbanization processes extend into rural spaces. Examples from Esmeraldas province, Ecuador, are shown. A-more highly urbanised (rural) communities are characterised by a higher population density with neighbourhoods and provision of urban services such as electricity, piped water, roads, and socioeconomic and lifestyle indicators not dependent on agricultural activities. Bmedium urbanised communities are characterised by lower population density, limited services but generally electricity, few houses constructed with cement, and an economy and lifestyle largely dependent on agricultural activities. C -Low urbanised communities are characterised by low population density, use of traditional materials for housing, no urban services or road access, and an exclusively agricultural economy. process, especially from rural to urban areas, involves changes in exposures to environmental and social factors such as pollution, housing, diet, and accessibility to health services, all of which are potential determinants of asthma. Studies in Ecuador have considered the effects of internal migration on asthma prevalence: crosssectional analyses have evaluated migration patterns in rural and urban areas and showed that children living in an urban area with a history of rural migration had a higher prevalence of asthma compared with the non-migrant population, 73,74 while a higher prevalence of childhood asthma in rural areas was associated with the absence of the mother. Mothers migrate to urban areas searching for work, leaving their children to be cared for by other family members. 73 These observations illustrate how social patterns associated with rural-urban migration, such as the feminization of migration and internal migration may contribute to temporal and geographical differences in asthma prevalence between urban and rural areas.

| Obesity
Obesity is increasing fast in LA countries. 75,76 Although studies in different settings have shown an association between asthma and obesity, 77,78 the causal nature of this association is unclear: obesity may trigger or aggravate wheezing/asthma, while wheezing/asthma may also contribute to obesity through, for example, reduced physical activity. 79 However, longitudinal studies indicate that obesity precedes asthma onset. 80 Similar observations have been reported in Brazil 81,82 and elsewhere in LA. 83,84 Obesity-related asthma has been linked to non-eosinophilic phenotypes (based on the pattern of inflammatory cells in induced sputum) that tend to be refractory to treatment. 85 An analysis in Brazilian children indicated that obese asthmatics were more likely to have non-atopic disease. 81

| Dietary patterns
Adopting a so-called Western lifestyle includes changes in diet and increased consumption of highly processed foods. 86 86,88 In contrast, higher intakes may have beneficial effects on the modulation of oxidative lung stimuli, thus decreasing airway hyperactivity, wheezing symptoms, and asthma. 89 For example, low serum zinc levels were associated with a doubling of wheeze prevalence. 90 Inverse associations have been demonstrated between a Mediterranean dietary pattern and asthma in Mexican children, 91 while fish consumption was associated with reduced risk of asthma symptoms, particularly non-atopic wheeze/asthma. 82 A recent study in children in Puerto Rico provided evidence that an effect of healthier diet in reducing asthma risk might be associated with a reduction in plasma levels of the inflammatory cytokine, IL-17-F 92 4.2 | The role of stress and other psychosocial problems on asthma/allergy

| Mental illness and psychological stress
There is a well-established relationship between psychological factors and asthma. 87 Studies in LA have reinforced the role of stress and other psychosocial problems as determinants of asthma prevalence (Table 1). In Brazil, asthma symptoms were more frequent in children of mothers with common mental disorders in a setting where children were typically exposed to intrafamilial and community violence and had a high frequency of behavioural problems often accompanied by depression, anxiety, and stress. [93][94][95][96][97][98][99] Interestingly, maternal mental illness predicted the development of asthma symptoms in children and adolescents. 100 Asthma itself may also increase the risk of mental disorders. 101 Multiple social and stress factors such as inequalities in health care access, exposure to stressors such as personal or community violence, individual and parental mental illness or behavioural problems 84,96,97,102,103 could contribute to asthma risk. LA is the most urbanized, unequal, and violent region globally, and where some of the highest prevalence rates for childhood asthma have been reported. 104 Associations between several mental disorders and asthma have been reported in LA populations. 105,106 A study of adults from São Paulo, Brazil, showed that anxiety with or without depression was associated with uncontrolled asthma. 107 A longitudinal analysis of asthmatic children in Salvador, Brazil, showed a reduced chance of remission and greater risk of developing severe symptoms among children internalizing problems. 99 Policies to prevent domestic and community violence can be justified on public health grounds because of the detrimental effects on mental health and asthma risk. 108    Europe and forced migrations from Africa since the 16th Century. 112 Population genetics and ethnic-racial characteristics differ greatly across countries in the region and likely contribute to differences in risk of asthma and allergy. shown to be associated with asthma and/or atopy. [115][116][117][118][119][120] Findings are summarized in Table 2. Americans. 123 Greater diversity among participants of genetic studies will improve our understanding of genetic structure across populations and ensure that genomic studies are more generally representative. 118,121,124,125 An important unresolved question was whether the genetic variants linked to asthma in HICs were also important in high prevalence populations in LA. The first GWAS done in an LA population identified two novel regions of the genome to be associated with asthma symptoms, 14q11 and 15q22. 125 These regions include genes involved in the modulation of inflammatory and immunological responses, such as LTB4 (leukotriene beta 4 receptor) TRA (T cell alpha receptor) and FOXB1 (forkhead box). The GWAS was able to identify significant associations of asthma with intergenic variants between genes DAD1 and OXA1L. A candidate gene analysis of variants in these 2 genes showed associations with asthma, atopy, and Th1 and Th2 cytokines production. Further polymorphisms in both genes affected gene expression levels and DAD1 was over-expressed in asthmatics. 116 Using the same GWAS, variants in the 17q12-21 locus were analysed, and among these, three on OMRDL3 and one on TOP2A gene were associated with childhood asthma. 126

| GWAS and asthma-related traits
Genetic associations with lung function using a GWAS approach in LA populations showed associations of lung function with a novel locus on chromosome 19 127,128 in Peruvian children and with four loci in an analysis of greater than 7000 asthmatics including Brazilians in the Consortium on Asthma among African ancestry Populations in the Americas (CAAPA). The latter analysis also identified two novel loci (8p23 and 8q24) that may be specific for asthma in populations with African ancestry. 129,130 Airways response to short-acting β2-adrenergic receptor agonists (SABA) has been shown to vary by ethnicity, 131 and among Latinos at least 15 genetic variants, including several in the 10q21 locus, have been associated with response to SABA. [132][133][134] Further, GWAS analyses that included Hispanics/Latinos showed variants associated with asthma exacerbations. [130][131][132][133]135  T A B L E 2 Summary of findings of associations between genetics and asthma in Latin America.

| Role of African ancestry
The question has been raised of whether genetic determinants of asthma in LA populations are related to a high contribution of African ancestry in population genomes. Although asthma prevalence is low (but increasing) in many African countries, individuals of African ancestry living in HICs suffer high prevalence and morbidity. 136,137 It has been suggested that individuals of African ancestry might have a higher frequency of immunity-related genetic variants promoting inflammatory responses through evolutionary adaptation of African ancestors to an environment with a high infectious diseases burden, particularly with parasites. 138 African ancestry is a risk factor for asthma in Brazilians 139 and other Latino populations. 136,140 In a population of children living in Salvador, Brazil, with a high level of African admixture, African ancestry was associated with reduced SPT but increased non-atopic asthma. 125 An admixture mapping metaanalysis that included 5 studies of childhood asthma with almost 4000 LA subjects, showed that ancestry at the locus 18q21 was associated with asthma. Native American ancestry was associated with an increased risk, while European ancestry was associated with protection from asthma. 141 This analysis also indicated that multiple ancestry-informative noncoding variants upstream of SMAD2 might have a role in asthma susceptibility. Admixture mapping of Brazilian children identified that African ancestry at the loci 17q21.31, 10q22.2, and 2p23.1 were associated with lower lung function. 126 Further, equations for predicting lung function in children, based on genetic ancestry have proven to be more accurate than standard models that use ethnic-racial classification. 142 The observation in

| Gene-environment interactions
There is a growing recognition of the importance of gene-environment interactions as determinants of allergic disease. 144,145 A genome-wide interaction study from Puerto Rico showed that dust mite allergen exposure appeared to modify the effect of a variant on chromosome 8q24.13 on FEV 1 in asthmatic children. 146 In Brazil, protection against asthma and atopy attributed to variants on the genes for leptin (LEP) and adiponectin (ADIPOQ) were lost in overweight individuals. 147 A study among Puerto Rican children exposed to violence showed an association between greater methylation of the anxiety regulating gene, ADCYAP1R1, and asthma. 148  Adherence was associated with favourable outcomes in both studies.
The definition of severe asthma has changed over time. The current definition adopted by the Global Initiative for Asthma (GINA) 158 requires laborious and lengthy clinical workup and follow up. There is no reliable population-based estimate of prevalence of severe asthma in LA using this latest definition 158 However, an analysis of large European and Brazilian severe asthma cohorts showed them to be remarkably similar in terms of clinical characteristics, despite marked ethnic, socioeconomic, and environmental differences. 159 Such an observation supports the concept of a single disease with several phenotypes rather a syndrome of multiple diseases.

| Asthma costs and implementation of good practice
Direct and indirect economic costs of asthma affect families and health systems but can be reduced by cost-effective interventions. 160 In Brazil, a greater proportion of family income is taken up by asthma costs in families with a asthmatic child or adolescent compared to those with an adult with asthma, 161 while a study in Colombia showed an association between disease severity and family costs that reached up to $2235 annually. 162   adequate disease management including ICS, and reduced exposure to environmental triggers such as tobacco smoke, future interventions for disease prevention will likely require a much better understanding of how specific environmental exposures interact with genetic susceptibility to cause disease.

CONFLICT OF INTEREST STATEMENT
The authors declare that they have no conflict of interest.

DATA AVAILABILITY STATEMENT
Data sharing not applicable to this article as no datasets were generated or analysed during the current study.